Glycopeptide antibacterial compounds, compositions containing same and methods of using same

ABSTRACT

The present invention relates to vancomycin analogs in which the vancosamine residue is substituted with a lipid-like substituent that includes a first aryl moiety and a second aryl moiety joined together by a flexible linker moiety, that is not a single bond directly joining the first aryl moiety and the second aryl moiety, and a glucose C-6 substituent modified to be other than the naturally occurring hydroxyl group, or pharmaceutically acceptable salts thereof.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of the filing date ofProvisional Application Serial No. 60/134,841, filed May 19, 1999, under35 USC 119.

FIELD OF THE INVENTION

[0002] The present invention relates to novel derivatives of naturalproducts, methods for their preparation, and the determination of theiractivity. In particular, the present invention relates to novelderivatives of glycopeptide antibiotics, such as vancomycin, methods fortheir preparation and their uses for the treatment of bacterialinfection.

[0003] In the preferred embodiment, the present invention relates tovancomycin-derived glycopeptide antibacterial agents, which arecharacterized by a heptapeptide structure that is covalently linked toat least one saccharide group. The saccharide group(s) can besubstituted with various substituent groups as described herein.

BACKGROUND OF THE INVENTION

[0004] An example of a known glycopeptide antibiotic is vancomycin,which contains a disaccharide substituent linked to a heptapeptidestructure. See Malabarba A., et al., Med. Res. Rev., 17(1):69-137(1997a); Nagarajan R. et al., J. Chem. Soc. Chem. Comm. 1306-1307(1988);Nagaranjan R., Antimicr. Agents Chemother., 35:605-609 (1991); andNagaranjan R., J. Antibiotics, 46:1181-1195 (1993). Vancomycin iseffective against gram positive bacteria. However, vancomycin resistantstrains have been recently observed, thus increasing the need for newand effective therapeutic agents.

[0005] The glycopeptides of the present invention are useful againstmany gram positive microorganisms, including vacomycin resistantenterococcus (VRE), methicillin resistant Staphylococcus aureus (MRSA),methicillin resistant Staphylococcus epidermidis (MRSE), and methicillinresistant coagulase negative Staphylococci (MRCNS). The antibacterialcompounds of the present invention thus comprise an important newcontribution to the development of therapeutic regimens for treatinginfections caused by these difficult to control pathogens and resistantstrains.

[0006] There is an increasing need for agents effective against suchpathogens, which are at the same time relatively free from undesirableside effects. Moreover, the physicochemical and pharmacologicalcharacteristics of candidate drugs, including their solubility, charge,hygroscopic characteristics, lipophilicity, bioavailability, tissuedistribution, serum half-life and the like can play important roles indetermining the success or failure of a candidate drug in the clinic.For example, it has been reported that a vancomycin analog in the PhaseIII clinical studies, which bears a chlorophenylbenzyl (also referredelsewhere in this application as chlorobiphenyl; other substituents aredescribed in, e.g., Rodriguez, M. J., J. Antibiotics, 51(6):560-569(1998)) substituent on the amine nitrogen of vancosamine and a freehydroxyl group on the C-6 position of glucose, exhibits a serumhalf-life in excess of two weeks. It has also been reported that tracesof this vancomycin analog can be detected in patients up to a year afterdrug administration. Clearly, should a patient experience any adversereaction to any drug, it would be beneficial if the patient's body couldmetabolize and/or clear the drug relatively quickly, e.g., within about24 or less, preferably within about 12 hours or less, most preferablywithin about 6-8 hours or less.

[0007] It should be noted that antibiotics of the type that includevancomycin are typically administered parenterally, that isintravenously. Hence, a relatively high clearance rate would nottypically be a disadvantage, and as stated above, would be of potentialgreat benefit to certain patients. Such intravenous formulations imposecertain requirements on a drug, not the least of which is adequatesolubility in the formulation medium. Thus, poorly soluble drugs may beunsuitable as a practical matter because the clinician is unable todissolve the drug in a formulation, much less deliver adequate amountsof the drug via intravenous drip. Generally, the pH of the formulationis buffered to correspond to physiological pH, which is about 7.4. Whilesome leeway is possible in the pH of an intravenous formulation, pain atthe site of injection typically limits the useful range of pH to no lessthan about 5 to no greater than about 8. Preferably, the pH of anintravenous formulation ranges from about 6-8, more preferably fromabout 7-8 and most preferably at or about physiological pH (e.g., about7.2-7.6).

[0008] Hence, there has been an on-going search for compounds thatexhibit not only increased potency against resistant strains but alsothe physicochemical and pharmacological characteristics that enhance theeffectiveness of a candidate compound and which may determine ultimatelyits acceptance in the clinic and resulting commercial success.

SUMMARY OF THE INVENTION

[0009] The present invention provides new analogs of vancomycin, whichexhibit enhanced biological activity and improved physicochemical andpharmacological characteristics. The overall properties of these analogsexhibit substantial potential as drug candidates for treating infectionscaused by certain pathogens, including various strains of drug resistantbacteria. Accordingly, a general method is provided for the preparationof such compounds, along with methods of using them for the treatment ofvertebrate conditions, including those afflicting mammals and especiallythose suffered by humans. Such conditions typically, although notexclusively, involve infections and other pathological conditions causedby bacteria and other microorganisms.

[0010] In particular, it has been observed that certain substituentspositioned at the amine nitrogen of vancosamine and at the C-6 positionof the glucose of vancomycin provide enhanced biological activityaccording to in vitro and in vivo assays and give rise to desirablephysicochemical and pharmacological characteristics, all of whichimprove a candidate drug's chances of success beyond the lab bench andin the clinic. More particularly, the present invention provides forlipid-like substituents on the amine nitrogen of vancosamine, whichinclude at least two aryl moieties that are joined (i.e., covalentlybound) together with a flexible linker moiety. By “lipid-like”substituent is meant a “lipophilic” substituent which refers to thetendency of the compound or substituent thereon to lack an affinity for,to repel or to fail to absorb water, or to be immiscible in water. Theterm “lipophilic” is not meant to exclude compounds or substituentsthereon that are not completely immiscible in water. By “flexiblelinker” is meant that the linker or linking groups provides at leastsome degree of flexible movement in the substituent containing thelipid-like substituent. The flexible linker moiety joining the two arylmoieties of the lipid-like substituent on the vancosamine nitrogen isnot a single bond directly joining the two aryl moieties. The flexiblelinker moiety appears to increase the lipophilicity of the molecule, asa whole, while potentially providing a site of attack for the metabolicand/or clearance processes of the body.

[0011] While a wide range of flexible linker moieties are potentiallyuseful in the present invention, such as alkylene groups, alkyleneethers, alkylene thioethers, ethers, thioethers, acyls, sulfonyls,sulfoxides, alkylene amines, unsaturated aliphatic groups and the like,the preferred embodiments are those that (together with at least thefirst or second aryl moiety and possibly other functional groups presentin the substituent) give rise to benzyl, benzylamino, benzyloxy,benzylthioether groups, phenyl ketones, or combinations thereof.Doubtless, one of ordinary skill in the art could contemplate otherflexible linker moieties, which could give rise to increasedlipophilicity and increased likelihood of breakdown/clearance by thebody. The same or a different flexible linker moiety is also present tojoin the amine nitrogen of vancosamine to the first aryl moiety part ofthe lipid-like substituent. In a preferred embodiment of the invention,the lipid-like substituent comprises the formula K—Ar₁-Z-Ar₂, as definedfurther below but which generally includes first and second arylmoieties, Ar₁ and Ar₂, and flexible linker moieties K and Z, providedthat Z is not a single bond directly joining Ar₁ and Ar₂.

[0012] It has been observed that of the wide range of possiblesubstituents that can be positioned at the glucose C-6 position ofvancomycin, polar substituents (that is, substituents that bear a chargeor possess the capacity to bear a charge, either positive or negative,at some useful range of pH, but preferably at or about physiological pH)enhance biological activity and/or provide advantageous physicochemicaland/or pharmacological characteristics. The term “polar” as used hereinto describe a compound of the present invention or a substituentthereon, refers to the tendency of the compund or substituent thereon tohave an affinity for, to attract or to absorb water, or to be misciblein water. The term “polar” is not meant to exclude compounds orsubstituents thereon that are not completely miscible in water. Mostpreferably, the polar substituent is part of an N-substituent (that is,an amine or amine based substituent) at the C-6 position, including butnot limited to a free amine, substituted amines, alpha-amino acidamides, carboxylic acid amides (e.g., the carboxylic acid amide obtainedfrom the reaction of a C-6 amine with for example succinic acid, otherdiacids, anhydrides, or other bifunctional acids), quaternary ammoniumsalts and the like. In particular, when not a free amine at the glucoseC-6 position, the invention contemplates those substituents that can bejoined to the amine group at the C-6 position of glucose and which (i)introduces a wide variety of functional groups, as part of or which canbe added to the substituent, and (ii) also provides for one or moreprimary or secondary amine sites at a distal position (that is, aposition in the substituent which is removed from the C-6 amine by twoor more carbon atoms or in which the amine site is separated from theC-6 amine by three or more chemical bonds). Still in other embodimentsof the invention, the polar substituent possesses polar groups, such asC(O), C(S), NH₂, NHR₂ groups and the like and combinations thereof,which may not ordinarily be charged. An example of such a polarsubstituent is urea or thiourea. It should be understood that the polarsubstituent contemplated by the present invention does not include thenaturally occurring substituent at glucose C-6 of vancomycin, which is ahydroxyl group.

[0013] The preferred vancomycin compounds of the invention, includingtheir pharmaceutically acceptable salts, are represented by the generalFormula 1, presented below:

[0014] in which R represents a polar substituent and K—Ar₁-Z-Ar₂represents a lipid-like substituent, as described above.

[0015] The invention is also directed to pharmaceutical compositions,including enteral and parenteral formulations of the compounds disclosedherein. Also disclosed are methods of determining the biologicalactivities of the various compounds of interest to the invention, aswell as those of lesser interest. Methods of preparing the compounds andof utilizing same in a treatment regimen are also described andcontemplated.

[0016] A more detailed description of the preferred embodiments of theinvention follows for the benefit of the reader. Additional objects ofthe invention will become apparent to the reader after consideration ofthe entire disclosure.

DETAILED DESCRIPTION OF THE INVENTION

[0017] As stated above, it has been observed that certain vancomycinanalogs bearing vancosamine lipid-like substituents of the formulaK—Ar₁-Z-Ar₂ possess enhanced biological activity relative to thoseconventional substituents that do not fall within the scope of theformula. These vancomycin analogs consistently exhibit at least a two-to four-fold increase in activity over those vancomycin analogs bearingsubstituents known in the art, especially in those bacterial strainsthat exhibit the greatest resistance to vancomycin or teicoplanin. Thesestrains include CL 4931, CL 5053, CL 5242 and CL 4877. See, Example 5.8,Table 3 and Table 4, below. Moreover, it is anticipated that improvedphysicochemical and pharmacological properties of the vancomycin analogsof the invention, including at least improved solubility characteristicsand greater clearance rates, will contribute to a higher likelihood ofsuccess for these compounds in the clinic.

[0018] Broadly speaking, the constituents of the lipid-like substituent,K—Ar₁-Z-Ar₂, can be the following:

[0019] K and Z can be the same or different and selected from anylinking group which will provide the characteristics of flexibilityrequired for the flexible linker. Especially preferred groups of thistype comprise carbonyl, sulfonyl, (C₁₋₆)alkylene, (C₁₋₆)alkyleneoxy,oxy(C₁₋₆)alkylene, (C₁₋₆)alkyleneamino, amino(C₁₋₆)alkylene,(C₁₋₃)alkyleneoxy-(C₁₋₃)alkylene, (C₁₋₆)alkylenethio,thio(C₁₋₆)alkylene, (C₁₋₆)alkylenecarbonyl, aminocarbonyl orcarbonylamino, (C₁₋₆)alkyleneaminocarbonyl, aminocarbonyl(C₁₋₆)alkylene,oxy, oxycarbonyl or carbonyloxy, (C₁₋₆)alkyleneoxycarbonyl,oxycarbonyl(C₁₋₆)alkylene, aminosulfonyl, or sulfonylamino,

[0020] Ar₁ and Ar₂ can be the same or different and selected fromaromatic or heterocyclic groups, each optionally monosubstituted,disubstituted, or trisubstituted with R₁; wherein

[0021] R₁ can be halo; R₂; CN; NO₂; CF₃; OCH_(x)F_((3-x)(x=0-3));NHSO₂R₂; OR₂, SR₂; N(R₂)₂; N⁺(R₂)₃; C(O)N(R₂)₂; SO₂N(R₂)₂; heterocyclic;CO₂R₂; C(O)R₂; OC(O)R₂; NR₂C(O)R₂; or NHC(O)R₂; and wherein R₂independently (where more than one R₂ is present) represents H, aryl,straight or branched (C₁₋₆) alkyl, arylalkyl, heterocyclic, heterocyclic(C₁-C₆) alkyl, aroyl, alkanoyl, alkanoyloxy, alkanoylamido,alkylsulfonyl, arylsulfonyl; and when two R₂ groups are present, theymay optionally be linked by one or more covalent bonds to form one ormore rings, which may be aromatic, aliphatic, or heterocyclic.

[0022] In a preferred embodiment of the invention, the polarsubstituent, R, has the formula:

[0023] in which the groups R₃ and R₄ may independently be present orabsent and, if present, may be the same or different and selected fromH, alkyl, aryl, heterocyclic, aralkyl, heterocyclicalkyl, alkylcarbonyl,arylcarbonyl, heterocycliccarbonyl, aminocarbonyl, substitutedaminocarbonyl, substituted oxycarbonyl, alkylsulfonyl, arylsulfonyl,heterocyclicsulfonyl, aminosulfonyl, substituted aminosulfonyl, amidino,or substituted amidino, said alkyl, aryl, heterocyclic, arylalkyl,heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, or heterocycliccarbonylbeing optionally substituted with 1-3 groups of R₁; and wherein R₃ andR₄ may be linked to one another or to one or both of the others by oneor more covalent bonds to form one or more aryl or heterocyclic rings of3-20 members, optionally comprised of C, N, O, or S. Preferably R is NH₂or substituted NH₂

[0024] Examples of preferred polar substituent groups are provided inthe Tables and the Chart included in this disclosure, which also provideexamples of preferred lipid-like substituents having two or moreflexible linkers.

[0025] The term “alkyl” refers to a monovalent alkane (hydrocarbon)derived radical comprising 1 to about 20 carbon atoms connected bysingle or multiple bonds, unless otherwise indicated. The alkyl groupmay be straight, branched, or cyclic. Examples of alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl, butyl,secbutyl, t-butyl, pentyl, cyclopentyl, hexyl and cyclohexyl. The term“alkylene” refers to a hydrocarbon radical comprising 1 to about 20carbon atoms connected by single or multiple bonds, unless otherwiseindicated, and which is bound to other functional or chemical groups ofthe molecule at least at two sites. Examples of alkylene groups include,but are not limited to, —CH₂—, —CH₂CH₂— —CH₂CH₂CH₂— —CH₂ (CH₃)CH₂—, andthe like, wherein each dash represents a point of attachment to anotherchemical or functional group of the molecule. When substituted, alkyland alkylene groups may be substituted with up to three substituentgroups, selected from Ra and Rh, as defined above, at any availablepoint of attachment. When an alkyl group is described as beingsubstituted with an alkyl group, such a phrase is used interchangeablywith “branched alkyl group.”

[0026] The term “cycloalkyl” is a species of alkyl and is a groupcomprising about 3 to about 15 carbon atoms, without alternating orresonating double bonds between carbon atoms. It may also contain from 1to 4 fused rings.

[0027] The term “aryl” refers to a group derived from a non-heterocyclicaromatic group having from six to about twenty carbon atoms and from oneto four rings, which may be fused, connected by single bonds, or both.An aryl group may be substituted by one or more of alkyl, aralkyl,heterocyclic, heterocyclicalkyl, heterocycliccarbonyl, halo, hydroxyl,protected hydroxyl, amino, nitro, cyano, alkoxy, aryloxy, aralkyloxy,aroyloxy, alkylamino, dialkylamino, trialkylammonium, alkylthio,alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl,aroyl, aralkanoyl, alkyloxycarbonyl, aralkyloxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl and the like.

[0028] The term “aralkyl” refers to an alkyl group bearing an aryl groupsubstituent.

[0029] The term “heterocyclic”, “heterocycle” or “heteroaryl” refers toa cyclic hydrocarbon group in which at least one of the ring positionsis occupied by a heteroatom. A heterocyclic compound may have from oneto about four rings, which may be fused, connected by single bonds, orboth. A heterocyclic group may comprise from three to about twenty ringatoms, which atoms may be chosen from carbon, nitrogen, oxygen, orsulfur as long as at least one heteroatom is present. A heterocyclicgroup may have up to 1, 2, or 3 double bonds per ring, thus allowing foran aromatic system. A heterocyclic group may be substituted by one ormore of alkyl, aryl, aralkyl, halo, hydroxyl, protected hydroxyl, amino,nitro, cyano, alkoxy, aryloxy, aralkyloxy, aroyloxy, alkylamino,dialkylamino, trialkylammonium, alkylthio, alkanoyl, alkanoyloxy,alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl,alkyloxycarbonyl, aralkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl and the like.

[0030] The term “alkenyl” refers to a monovalent alkene group comprisingup to about 20 carbon atoms which contains at least one double bondbetween carbon atoms. The alkene group may be straight chained or branchchained. Examples include vinyl, propenyl, butenyl and pentenyl groups.

[0031] The term “alkynyl” refers to a monovalent alkyne group comprisingup to about 20 carbon atoms which contains at least one triple bondbetween carbon atoms. The alkyne group may be straight or branchchained. Examples are propynyl, butynyl and pentynyl.

[0032] The term “heteroatom” means an atom other than carbon orhydrogen, but is generally associated with the atoms N, O, or S,selected on an independent basis.

[0033] The term “halogen” or “halo” refer to fluorine, chlorine,bromine, or iodine.

[0034] The terms “alkoxy,” “aryloxy” and “aralkyloxy” refer to achemical group in which an oxygen atom is covalently bound to an alkyl,aryl, or aralkyl group, respectively.

[0035] The terms “alkanoyl,” “aroyl” and “aralkanoyl” refer to chemicalgroups in which a carbonyl group is covalently bound to an alkyl, aryl,or aralkyl group, respectively.

[0036] The term “heterocyclicalkyl” or “heterocycliccarbonyl” refers tochemical groups in which a heterocyclic group is covalently bound to analkyl or carbonyl group, respectively.

[0037] When a group is termed “substituted,” unless otherwise indicated,this means that the group contains from 1 to 3 substituents thereon.

[0038] When a functional group is termed “protected,” this means thatthe group is in a temporary, modified form to inhibit the participationof the protected site in a particular reaction sequence intended toeffect some change elsewhere in the molecule. Suitable protecting groupsfor the compounds of the present invention will be recognized from thepresent application taking into account the level of skill in the art,and with reference to standard textbooks, such as Greene, T. W. et al.“Protective Groups in Organic Synthesis” Wiley, New York (1991). Inaddition, examples of suitable protecting groups are presentedthroughout the specification.

[0039] In some of the glycopeptide compounds of the present invention ahydroxyl-protect group might be required. Such conventional protectinggroups consist of known groups, which are used to protectively block thehydroxyl group during the synthetic procedures described herein. Theseconventional blocking groups are readily removable; i.e., they can beremoved, if desired, by procedures that will not cause cleavage or otherdisruption of the remaining portions of the molecule. Such proceduresinclude chemical and enzymatic hydrolysis, treatment with chemicalreducing or oxidizing agents under mild conditions, treatment with atransition metal catalyst, a nucleophile and catalytic hydrogenation.

[0040] Examples of suitable C-6 hydroxyl protecting groups include, butare not limited to, triethylsilyl, t-butyldimethylsilyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl,allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyland the like.

[0041] The glycopeptide compounds of the present invention are usefulper se and in their pharmaceutically acceptable salt and ester forms forthe treatment of bacterial infections in animal and human subjects. Theterm “pharmaceutically acceptable ester, salt, or hydrate” refers tothose esters, salts, or hydrated forms of the compounds of the presentinvention, which would be apparent to the medicinal chemist. Such formsinclude, but are not limited to, those that are substantially non-toxicand which may favorably affect the pharmacokinetic properties of saidcompounds, such as palatability, absorption, distribution, metabolismand excretion. Other factors, more practical in nature, which are alsoimportant in the selection, are cost of the raw materials, ease ofcrystallization, yield, stability, solubility, hygroscopicity andflowability of the resulting bulk drug. Conveniently, pharmaceuticalcompositions may be prepared from the active ingredients in combinationwith pharmaceutically acceptable carriers. Thus, the present inventionis also concerned with pharmaceutical compositions and methods oftreating bacterial infections utilizing as an active ingredient thenovel glycopeptide compounds of the present invention, particularly thevancomycin-like glycopeptide compounds disclosed herein.

[0042] The pharmaceutically acceptable salts referred to above alsoinclude acid addition salts. Thus, the Formula I compounds can be usedin the form of salts derived from inorganic or organic acids. Includedamong such salts are the following: acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate andthe like.

[0043] A strategy to introduce a suitable set of protecting groups andto differentiate the C-6 hydroxyl group from all other hydroxyl groupsof a glycopeptide having a hexose residue at amino acid number four (A₄)is illustrated below in Scheme 1, showing functionalization of theglucose C-6 hydroxyl of vancomycin, wherein Alloc-Su isN-(allyloxycarbonyloxy) succinimide.

[0044] In general, introduction of the substituent containing the linkergroup on the vancosamine nitrogen is preferably by reductive amination,either direct or to a peptide-protective species. In general,introduction of the polar group at C₆ is preferably by azidedisplacement/reduction, amine nucleophilic displacement, and/oracylation.

[0045] Protection of both amines by a similar group requires usingexcess acylation reagent while selective protection of the N-methylleucine residue is known, allowing selective functionalization of thevancosamine amine group. See, Pavlov et al., J. Antiobiotics, 1993, 46,1731. Selectively, introducing the mesitylenesulfonyl group at theglucose-6-position differentiates this position from the other hydroxylgroups and allows further reaction to displace the mesitylenesulfonylgroup, affording many derivatives. A variety of functional groups areintroduced at the glucose-6 position by using common methods fornucleophilic displacement of primary arylsulfonyl groups directly, or byfurther synthetic modification of initial displacement products,including azido and iodo groups. For example, the iodo group isdisplaced by a variety of nucleophiles to produce additional C-6derivatives. A preferred nucleophile is a thiol compound, especially aheterocyclic thiol. Modification of an azido group at the 6-position isperformed, e.g., by reducing the azido group to an amino group, which inturn is functionalized by means of reductive alkylation, nucleophilicsubstitution, or other amino-group reactions well known to those skilledin the art. These approaches are illustrated in many examples. In apreferred embodiment of the invention, an azido group is partiallyreduced by reaction with a phosphine compound to produce animinophosphorane.

[0046] More specifically, the amino substituents of vancomycin areprotected as indicated while introducing a mesitylenesulfonyl functionalgroup at the C₆ position. The allyloxycarbonyl groups are introduced byreaction of vancomycin hydrochloride in aqueous solution withN-(allyloxycarbonyloxy) succinimide contained in an organic solvent suchas acetone. A preferred procedure is to treat the aqueous solution ofvancomycin with the organic solvent solution of succimide.

[0047] This resulting solid product is reacted with an allyl halidereactant such as allyl bromide in the presence of an alkali metalbicarbonate to form an allyl ester of the carboxyl and protect thatposition. The resulting allyl ester is then reacted with a compoundwhich will introduce a functional group such as mesitylenesulfonylchloride by reaction in a solvent such as pyridine so as to introducethe mesitylenesulfonyl moiety at the C₆ hydroxy. This compound is thenreacted with an alkali metal halide such as KI to introduce I at the C6position. The protective allyl group is then removed conventionally suchas with a palladium compound and a phosphinobutane.

[0048] In the next step, the intermediate is reacted withallyloxycarbonyl succinimide to protect the secondary nitrogen whileleaving the primary nitrogen unprotected. At this stage the intermediatecan be reacted with an aldehyde such as the benzyloxybenzaldehyde as inExample 5.4 to introduce a benzyloxybenzyl group at the vancosaminenitrogen. Similarly, other aldehydes can be reacted with the same orsimilar intermediate to form other derivatives, such as the use of thealdehyde phenylbenzaldehyde to introduce the K—Ar₁-Z-Ar₂ moieties of thecompounds of the tables. Similarly, aldehydes or other reactivecompounds can be used in a known manner to introduce the K—Ar₁-Z-Ar₂derivatives of the compounds of the tables.

[0049] After the vancosamine is suitably substituted, the intermediateis reacted with an alkali azide to form an azide which is then reactedwith a phosphine for conversion to the amine. Obviously substitutedamines such as the substituents shown in this position in the compoundsof the tables can be provided using these reations.

[0050] After the vancosamine amine polar group is introduced, theprotected secondary amine is deprotected to produce the final product.

[0051] A similar procedure for preparation of the glycopeptides of theinvention is shown in the following reaction scheme 2 where K—Ar₁-Z-Ar₂is as described above, and Fmoc is Fluorenylmethoxycarbonyl, and NR₂R₂ ¹is the reactant to introduce the amine substituent. In this reactionwith XCHO, deblocking is carried out as described, and X is theK—Ar₁-Z-Ar₂ substituent on the vancosamine nitrogen.

[0052] In a preferred embodiment of the invention, the vancomycin analogand its pharmaceutically acceptable salt is described by the Formula 1,depicted above, in which the group R represents a group

[0053] in which R₃ and R₄ may independently be H, (C₁₋₁₂)alkyl,aryl(C₁₋₃)alkyl, heterocyclic(C₁₋₃)alkyl, (C₁₋₁₂)alkylcarbonyl,arylcarbonyl, or heterocyclic-carbonyl, said alkyl, aryl,heterocyclicalkyl, being optionally substituted with 1-3 groups of R₁;or in which R₃ and R₄ may be linked by one or more covalent bonds toform one or more rings of 3-20 members each;

[0054] K is a carbonyl, sulfonyl, (C₁₋₃)alkyl, Oxy(C₂₋₃)alkyl,(C₁₋₃)alkylcarbonyl, or (C₁₋₃)-alkyloxycarbonyl;

[0055] Z is a carbonyl, sulfonyl, (C₁₋₃)alkyl, (C₁₋₃)alkyloxy,Oxy(C₁₋₃)alky (C₁₋₃)-alkyloxy(C₁₋₃)alkyl, aminocarbonyl, carbonylamino,aminosulfonyl or, sulfonylamino;

[0056] Ar₁, is aromatic or heterocyclic, each optionally monosubstitutedor disubstituted with R₁; and

[0057] Ar₂ is aromatic or heterocyclic, each optionally monosubstituted,disubstituted, or trisubstituted with R₁;

[0058] R₁ is halo including chloro, bromo, iodo or fluoro, R₂, CN, CF₃,OCH_(x)F_((3-x)(x=0-3)), NHSO₂R₂, OR₂, SR₂, N(R₂)₂, N⁺(R₂)₃, C(O)N(R₂)₂,SO₂N(R₂)₂, heterocyclic, CO₂R₂, C(O)R₂, OC(O)R₂, or NHC(O)R₂, andwherein R₂ independently represents H, aryl, straight- or branched-chain(C₁₋₃)alkyl group, aryl(C₁₋₃)alkyl, heterocyclic,heterocyclic(C₁₋₃)alkyl, alkylsulfonyl, arylsulfonyl and the like. Whentwo R₂ groups are present, they may optionally be linked by covalentbonds to form one or more rings. Said rings may be aromatic, aliphatic,or heterocyclic.

[0059] In yet another preferred embodiment of the invention, the group Kis a carbonyl, sulfonyl, or CH₂ group. The R group is more preferablyNH₂.

[0060] A representative example of a preferred embodiment of thevancomycin analog compounds of the present invention is depicted below:

[0061] This compound is Entry Number 13 in Table 2.

[0062] The synthesis of the target compound is completed by removing anyprotecting groups that may be present in the penultimate intermediateusing standard techniques that are well known to those skilled in theart. The deprotected final product is then purified, as necessary, usingstandard techniques such as ion exchange chromatography, reverse phaseHPLC, MPLC on reverse phase polystyrene gel and the like, or byrecrystallization.

[0063] The final product may be characterized structurally by standardtechniques such as NMR, IR, MS and UV. For ease of handling, the finalproduct, if not crystalline, may be lyophilized from water to afford anamorphous, easily handled solid.

[0064] The compounds of the present invention are valuable antibacterialagents active against various gram-positive and, to a lesser extent,gram-negative bacteria. Accordingly, these compounds find utility inhuman and veterinary medicine.

[0065] Many of compounds of the present invention are biologicallyactive against VRE/MRSA/MRCNS. In vitro antibacterial activity isgenerally predictive of in vivo activity. It is contemplated that thecompounds of the present invention will be administered to a mammalinfected with a susceptible bacterial organism.

[0066] Using standard susceptibility tests, the compounds of theinvention are determined to be active against VRE/MRSA.

[0067] The compounds of the invention can be formulated inpharmaceutical compositions by combining the compound with apharmaceutically acceptable carrier. Examples of such carriers are setforth below.

[0068] The compounds may be employed in powder or crystalline form, inliquid solution, or in suspension. They may be administered by a varietyof means; those of principal interest include: topically, orally andparenterally by injection (intravenously or intramuscularly).

[0069] Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampoules, or in multidose containers.The injectable compositions may take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and may containvarious formulating agents. Alternatively, the active ingredient may bein powder (lyophilized or non-lyophilized) form for reconstitution atthe time of delivery with a suitable vehicle, such as sterile water. Ininjectable compositions, the carrier is typically comprised of sterilewater, saline, or another injectable liquid, e.g., peanut oil forintramuscular injections. Also, various buffering agents, preservativesand the like can be included.

[0070] Topical applications may be formulated in carriers such ashydrophobic or hydrophilic base formulations to provide ointments,creams, lotions, in aqueous, oleaginous, or alcoholic liquids to formpaints or in dry diluents to form powders.

[0071] Oral compositions may take such forms as tablets, capsules, oralsuspensions and oral solutions. The oral compositions may utilizecarriers such as conventional formulating agents and may includesustained release properties as well as rapid delivery forms.

[0072] The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated, the route and frequencyof administration, the sensitivity of the pathogen to the particularcompound selected, the virulence of the infection and other factors.Such matters, however, are left to the routine discretion of thephysician according to principles of treatment well known in theantibacterial arts. Another factor influencing the precise dosageregimen, apart from the nature of the infection and peculiar identity ofthe individual being treated, is the molecular weight of the compound.

[0073] The compositions for human delivery per unit dosage, whetherliquid or solid, may contain from about 0.01% to as high as about 99% ofactive material, the preferred range being from about 10-60%. Thecomposition will generally contain from about 15 mg to about 2.5 g ofthe active ingredient; however, in general, it is preferable to employdosage amounts in the range of from about 250 mg to 1000 mg. Inparenteral administration, the unit dosage will typically include thepure compound in sterile water solution or in the form of a solublepowder intended for solution, which can be adjusted to neutral pH and bemade isotonic.

[0074] The invention described herein also includes a method of treatinga bacterial infection in a mammal in need of such treatment comprisingadministering to said mammal a compound of Formula I in an amounteffective to treat said infection.

[0075] The preferred methods of administration of the Formula Iantibacterial compounds include oral and parenteral, e.g., i.v.infusion, i.v. bolus and i.m. injection.

[0076] The invention is further described in connection with thefollowing non-limiting examples.

5. EXAMPLES

[0077] 5.1. Preparation ofN,N′-Diallyloxylcarbonyl-glucose-C6-iodide-vancomycin Allyl Ester A

[0078] Step 1: N,N′-diallyloxycarbonyl Vancomycin (a)

[0079] To a solution of vancomycin-HCL (13 g, 8.7 mmol) in 105 mL wateris slowly added 80 mL acetone. A 30 mL aqueous solution of NaHCO3 (1.54g, 18.3 mmol) is then added over 5 minutes affording a thick whiteslurry. After stirring 10 minutes the suspension is treated with asolution of N-(allyloxycarbonyloxy)succinimide (18 g, 90 mmol) in 70 mLacetone. Within a few hours the reaction became clear and stirred atroom temperature for 36 hours. TLC (6:4:1, chloroform-methanol-water)shows no vancomycin (baseline) remaining and one predominantglycopeptide product (Rf=0.3). The crude reaction mixture is treatedwith 1-butanol (100 mL) and evaporated to dryness under reducedpressure. The solid is dissolved in 50 mL methanol and precipated byaddition to 300 mL diethyl ether. Any chunks are crushed and the whitesuspension allowed-to settled for 1 hour at 4° C. Approximately 200 mL,of the clear supernatant is decanted and the remaining suspensioncentrifuged and the supernatant decanted. The white solid is mixedvigorously with 240 mL acetone, the suspension centrifuged and thesupernatant decanted. The solid is dissolved in methanol, diluted with300 mL toluene and evaporated under reduced pressure affording (a) (15.5g, containing a trace of the NHS impurity) which could be used withoutfurther purification. If it is desirable removal of the NHS; the solidis dissolved in a minimum of methanol/DMF (1:1) and precipitated byaddition to water. The suspension is mixed well, the suspensioncentrifuged and the supernatant decanted. The white solid is dissolvedin methanol to combine fractions, diluted with excess toluene,evaporated under reduced pressure, and dried in vacuo. Preparation ofN-(allyloxycarbonyloxy)succinimide is reported in Int. J. PeptideProtein Res. 1991, 37, 556-564.

[0080] Step 2: N,N′-diallyloxylearbonyl-vancomycin Allyl Ester (b)

[0081] Compound (a) (5 g, 3 mmol) is dissolved in 28 mL DMSO under anargon atmosphere (1 hour with stirring). Powdered Na.HCO₃ (2.5 g, 30mmol) is added and the suspension stirred 10 minutes followed byaddition of allyl bromide (1.3 mL, 15 mmol). Stirring is continued for 7hours, at which time TLC shows the disappearance of (II) and onepredominate product. The reaction is slowly diluted with acetone (ca. 25mL) until the precipitate, formed upon addition, is just redissolved.This solution is vacuum filtered (removing the insoluble NaHCO₃) into aflask containing 200 mL acetone and 450 mL diethyl ether. The flask isswirled occasionally during filtrate addition to disperse the mixture ofwhite precipitate and oil that formed. The reaction flask and filter arerinsed with 10 mL acetone-methanol (1:1). The filtrate/suspension isstored at 4° C. for 16 hours with occasional swirling. The precipitateand oil coated the flask leaving a clear supernatant that is decanted.The solid mass is rinsed with acetone, dried under high vacuum, anddissolved in 10 mL DMF-methanol (1:1). This solution is precipiated byaddition to 180 mL water (600 mL in 6 centrifuge tubes). The suspensionis mixed, chunks crushed, centrifuged, and the supernatant decanted. Thesolids are combined in methanol-acetone, diluted with toluene,evaporated under reduced pressure, and dried in vacuo affording (b) (4.5g). TLC: Rf=0.67; (chloroform-methanol-water; 6:4:1). An analyticalsample is prepared by separation on HPLC; (Method A; 30 minutes lineargradient of 25% to 60% acetonitrile; flow rate=7.5 mL/min.) affording(b), Ret. time=24 minutes; LRESI-MS calc for 2:1655.5; [M+H]+=1657;[M-vancosamine+H]+=1431.

[0082] Step 3: N,N′-diallyloxycarbonyl-glucose-C6-mesitylenesulfonylVancomycin Allyl Ester (c)

[0083] To a stirred solution of compound (b) (370 mg, 0.22 mmol) in 2.5mL anhydrous pyridine under an argon atmosphere at 4° C. is added 0.5 mLof 1.4 M solution of mesitylenesulfonyl chloride in pyridine. Thetemperature is maintained at 4° C. for 24 hours at which time thereaction is precipitated by addition to 50 mL diethyl ether (2×25 mL intwo 50 mL centrifuge tubes). The suspension is centrifuged and thesupernatant decanted. The solids are combined by dissolving in methanoland evaporated under reduced pressure. Separation by HPLC (Method A; 40minutes linear gradient of 30% to 75% acetonitrile; flow rate=7.5mL/minutes) affords starting material (b) (64 mg) and (c) (202 mg, 50%,60% based on recovered (b). Ret. time=28 minutes; TLC:Rf=0.7(chloroform-methanol-water, 50:21:4). LRESI-MS calc forC86H97N9030SIC12:1837.5; [M+H]+=1839; [M-vancosamine+H]+=1614;[M-disaccharide+H]+=1267.

[0084] Step 4: N,N′diallyloxylcarbonyl-glucose-C₆-iodide-vancomycineAllyl Ester (A)

[0085] N,N′-diallyloxycarbonyl-glucose-C₆-mesitylenesulfonyl-vancomycinallyl ester (0.2 mmol, 367 mg) and KI (2 mmol, 332 mg) are heated in 4mL of DMF at 80° C. for 16 h. The reaction is allowed to reach ambienttemperature, and the product is precipitated by addition of 100 mL ofH₂O. The product is filtered, washed with water and dried under highvacuum, affording 310 mg of a white solid, A.

[0086] 5.2. Preparation of Glucose-C6-iodide-vancomycin B

[0087] N,N′-diallyloxycarbonyl-glucose-C₆-iodide-vancomycin allyl esterA (1.7 mmol, 310 mg) is dissolved in 4 mL of DMF containing piperidine(2 mmol, 211 μL). To the reaction mixture is added a 1 mL solution oftris(dibenzylideneacetone)-dipalladium(0) (0.04 mmol, 17 mg) and1,4-bis(diphenylphosphino)-butane (0.04 mmol, 17 mg) in THF, whichsolution is allowed to react for 5 min. prior to addition. After 1 h.the product is precipitated by addition of 100 mL of ether. The productis filtered and washed with additional ether to provide B. Retentiontime=0.73 min.

[0088] 5.3. Preparation of N′-allyloxycarbonyl-glucose-C6-iodovancomycinC

[0089] To a stirring solution of B (0.2 mmol, 3 10 mg) and NaHCO₃ (0.6mmol, 50 mg) in 10 mL of 1:1 dioxane/H₂O cooled in an ice bath is addeddropwise a solution of N-(allyloxycarbonyloxy)succinimide (0.3 mmol, 60mg) in 1 mL of dioxane. The reaction is allowed to stir overnight,during which time the solution reaches ambient temperature. The productis purified by reverse-phase HPLC, which after lyophilization affords103 mg of monoalloc C as the TFA salt. Retention time=1.29 min.

[0090] 5.4. Preparation ofN-4-(3-4-dichlorobenzyloxy)benzyl-N′-alloc-glucose-C6-iodovancomycin D

[0091] To a solution of C (0.035 mmol, 62 mg) and4-(3-4-dichlorobenzyloxy)benzaldehyde (0.25 mmol, 70 mg) in 2 mL of DMFcontaining 1% (v/v) of HOAc is added NaBH(OAc)₃ (0.25 mmol, 53 mg).After 2 h, an additional 50 mg of NaBH(OAc)₃ is added, and the reactionis allowed to stand at ambient temperature for 15 h. The product isprecipitated by addition of 60 mL of H₂O to the solution. The solid isfiltered and dried in vacuo, affording 56 mg of D as a white solid.Retention time=1.98 min.

[0092] 5.5. Preparation ofN-4-(3-4-Dichlorobenzyloxy)benzyl-N′-allyloxycarbonyl-glucose-C6-amino-vancomycinE

[0093] A solution of D (0.02 mmol, 37 mg) and NaN₃ (0.3 mmol, 20 mg) in1 mL of DMF is stirred at 60° C. for 4 h. The reaction is then stirredat 40° C. for an additional 15 h. The reaction mixture is allowed toreach ambient temperature and solid NaN₃ is removed by filtration. Theproduct is precipitated by addition of 40 nL of ether, filtered andwashed with methylene chloride. The resulting azidovancomycin isdissolved in 3 mL of 4:1 THF/H₂O, and Ph₃P(50 mg) is then added to themixture. The reaction is stirred for 16 h. at 40° C. Solvent is removedby rotary evaporation. The residue is triturated in methylene chlorideand filtered, affording 40 mg of E. Retention time=1.79 min.

[0094] 5.6. Preparation ofN-4-(3-4-Dichlorobenzyloxy)benzyl-N-glucose-C6-amino-vancomycin 13

[0095] To compound E in 9:1 (v/v) DMF/piperidine is added a 1 mLsolution in THF of tris(dibenzylideneacetone)-dipalladium(0) (0.01 mmol,4 mg) and 1,4-bis(diphenylphosphino)-butane (0.01 mmol, 4 mg), whichsolution is allowed to react for 5 min. prior to addition. After 1 h.the product is precipitated by addition of 10 mL of ether, filtered, andwashed with additional ether. The solid is taken up in DMF and filteredto remove residual Pd. Removal of solvent in vacuo affords 17 mg ofcrude 13. A 4 mg portion of crude material is purified by reverse-phaseHPLC to afford 1.4 mg of pure 13 as the TFA salt. Retention time=1.39min; Mass Spec. [M+H]²⁺ 856

[0096] 5.7. Preparation of Additional Compounds

[0097] Using methods similar to the method described above, compounds1-12 and 14-24 are prepared and purified using reverse phase HPLC. Theidentities of the chemical groups comprising the lipid-like substituent,K—Ar₁-Z-Ar₂, and the polar substituent R, in particular where R═NR₂R₃,are illustrated in Table 2, appended to the specification. Vancomycinanalogs comprising a more conventional substituent at the amine nitrogenof vancosamine are illustrated in Table 1. The retention times of eachof the compounds, as well as their putative molecular weights, are alsopresented in Tables 1 and 2. Of interest is the greater retention time(on average about a 17% increase in retention time) observed for thecompounds of Table 2 over the compounds of Table 1, regardless of thenature of the substituent on the glucose C-6 position. The retentiontimes support the proposition that the compounds of Table 2 exhibit anincreased lipophilicity over the compounds of Table 1.

[0098] The chemical names of the compounds listed in Table 2 are:Glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,13;N-(3-Pyridyl)methyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,17;N-Glycyl-glucos-6-ainino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin18;N-β-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin18;N-D-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,19; N-L-Prolyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, 18;N-P-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin, 19;N-L-Lysyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,20;N-L-(3-thiazolyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosaminovancomycin, 21;N-L-(2-thienyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,22;N-L-Asparagyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,23;N-D-(3-pyridyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,24.

[0099] These compounds exhibit desirable levels of antibiotic activitywhen tested against a panel of bacterial strains, including certainvancomycin-resistant strains, as described in greater detail, below. Thecompounds listed in Table 2 consistently provide for at least a two- tofour-fold increase in activity, however, compared to the compoundslisted in Table 1, at least for those strains of bacteria which exhibitthe greatest resistance to vancomycin and teicoplanin.

[0100] 5.8. In vitro Assay Utilizing a Panel of Bacterial Strains

[0101] 5.8.1. Assay Protocol

[0102] National Committee for Clinical Laboratory Standards (NCCLS)guidelines [Methods for Dilution Antimicrobial Susceptibility Tests forBacteria that Grow Aerobically-Fourth Edition; Approved Standard (NCCLSDocument M7-A4, January 1997)] are used to establish the assay, althoughvariations are made to optimize the published method according to thespecific needs of the present investigation.

[0103] The test panel currently includes eight enterococci and 13staphylococci, which are selected based upon their antibioticsusceptibility profiles. The methicillin-sensitive Staphylococcus aureus(MSSA) strain MB2985 (Smith isolate) is used to assesses the potentialfor serum protein binding of the compounds. The paired Gram-negativestrains ASP #49 (envA−) and ASP #50 (envA+) (M. Salvatore/N. Lee) areincluded to judge membrane effects. Table 3 presents a detaileddescription of the strains included in the panel, including some of thesources of the strains of bacteria.

[0104] Relevant antibiotic controls include the glycopeptide antibioticvancomycin and the penem antibiotic Schering 29482, which exhibitsreduced activity in the presence of Human Serum Albumin or Fraction V,due to binding of the antibiotic. The glycopeptide antibioticteicoplanin is included whenever possible.

[0105] 5.8.2. Recommended Sources of Supplies

[0106] Trypticase Soy Broth (TSB) (Source: BBL, Becton DickinsonMicrobiolgy Systems, Cockeysville, Md. 21030, U.S.A.)

[0107] Horse Serum (HS) (Source: GIBCO BRL Laboratories, Grand Island,N.Y. 14072, U.S.A.)

[0108] Mueller Hinton II Broth (MH II) (Source: BBL, Becton DickinsonMicrobiology Systems, Cockeysville, Md. 21030, U.S.A.)

[0109] Brain Heart Infusion Broth (BHI) and Brain Heart Infusion Agar(BHI Agar) (Source: Difco Laboratories, Detroit, Mich. 48232, U.S.A.)

[0110] Human Serum Albumin, Fraction V (HSA) (Source: CalbiochemCorporation, La Jolla, Calif. 92037, U.S.A.)

[0111] 5.8.3. Overnight Growth Medium

[0112] TSB, containing 10% HS* for vancomycin intermediate S.aureus/methicillin-resistant S. aureus (VISA/MRSA) strains, isinoculated from an appropriate source (frozen broth or agar slant) andgrown approximately 17 hr at 35° C. with shaking at 220 rpm. Culturesare grown in tubes with a volume of 5 ml for enterococci and 2 ml forall other strains.

[0113] 5.8.4. Culture Dilution

[0114] Four milliliter (4 ml) overnight culture is added to 36 mlphysiological saline to obtain tenfold dilutions (enterococci).Overnight culture (0.4 ml) is added to 39.6 ml saline to obtain 100-folddilutions (all strains except enterococci). Diluted cultures aremaintained on ice until time of inoculation of test plates.

[0115] 5.8.5. Plate Medium for Obtaining Titers of Overnight Cultures

[0116] The number of CFU/ml is determined on BHI agar plates, althoughthis is not done routinely because titers of overnight cultures arerelatively constant. The test media include:

[0117] BHI for enterococci and VISA/MRSA;

[0118] MH II (i.e., cation-adjusted Mueller-Hinton broth) for MRS, MSSand E. coli.;

[0119] MH II+HSA for MSSA is prepared as follows:

[0120] a. 2×MH+86 mg/ml HSA

[0121] b. Dissolve 4.3 g HSA in 50 ml autoclaved 2×MH II.

[0122] c. pH to 7.0 by adding 2M MOPS, sodium.

[0123] d. Filter sterilize using 0.22 μm Corning cellulose acetatefilter, used because of reported low protein binding.

[0124] e. 1×MH II+43 mg/mlHSA

[0125] f. Dilute the 2×medium twofold and filter as above.

[0126] 5.8.6. Preparation of Test Plates

[0127] Using a Denley liquid handling system (or similar automaticdevice), 100 μl×medium is added to each well in columns 2-12 of a96-well microtiter dish. Using a multichannel pipettor, 100 μl 2×mediumis added to each well in column 1. Plates may be filled on the day priorto assay, wrapped in plastic bags and refrigerated.

[0128] 5.8.7. Preparation of Antibiotics

[0129] Vancomycin, Schering 29482, and teicoplanin are prepared on aweight per volume basis using 10 mM 3-(N-morpholino)propane-sulfonicacid (MOPS) buffer pH 7. Test compounds are received in solution inappropriate solvent (typically as 1 mg/ml in DMSO) or are dissolved inappropriate solvent prior to further dilution in 10 mM MOPS buffer, pH7. Consistent with NCCLS guidelines, antibiotics are handled asepticallybut are not otherwise sterilized.

[0130] 5.8.8. Assay

[0131] 100 μl appropriately diluted antibiotic solution is added to thefirst well of the designated row of the 96-well microtiter dish andserially diluted by twofold across the row using the Denley liquidhandling system. With the aid of a Dynatech NEC 2000 inoculator, eachwell of the microtiter dish is inoculated with 1.5 μl diluted overnightculture, yielding approximately 1-5×106 CFU/ml for enterocoeci andapproximately 3-7×105 CFU/ml for all other strains. Dishes are placed instacks of no more than five, wrapped in plastic bags and incubated at35° C.

[0132] Indication of result(s) type (%INH, IC50, Zone size, etc.)

[0133] MIC=minimum inhibitory concentration

[0134] 5.8.9. Interpretation of the Results on the Basis of Activity

[0135] Presence or absence of growth is scored at 18-20 hr for strainMB2985 and for E. coli., at 22-24 hr for all other strains. MIC isdefined as the lowest concentration of antibiotic that allows no visiblegrowth following incubation. The compounds of the present inventiondisplay adequate improvement over the activity exhibited by the controlcompounds. In particular, the results of panel testing of compound 13are presented in Table 4.

[0136] 5.8.10. In vivo Mice Studies Protocol for theMethicillin-Sensitive

[0137]Staphylococcus aureus Septicemia

[0138] Selected compounds of the invention are tested in an in vivomouse model. Single dose subcutaneous antibiotic protection fromsepticemic infections is measured as described by Gill, C. J., J. J.Jackson, L. Gerckens, B. Pelak, R. Thompson, J. Sundelof, H. Kropp andH. Rosen. Antimicrob. Agents Chemother. 42:1996-2001 (1998). Survival ismonitored for seven days. ED₅₀'s and LD₅₀'s are determined by the methodof Knudsen and Curtis. J. Am. Stat. Assoc. 42:282-296 (1947). Septicemiais induced in 20 gram ICR (derived from CD-1) female mice byintraperitoneal infection with Staphylococcus aureus strain MB2985.Infection is given i.p. in Brain Heart Broth (BHB) at an infectiousinoculum of 1.8×10⁷ cfu/mouse. Drug is administered subcutaneouslyimmediately after the infection is initiated.

[0139] The MIC is determined by microdilution in Mueller-Hinton broth(MHB) according to the National Committee for Clinical LaboratoryStandards guidelines after incubation for 24 hours. Enterococci aretested in cation-supplemented Mueller-Hinton broth at 1.4×10⁵ cfu/ml.MIC is defined as the lowest concentration of antibiotic, which inhibitsvisible growth.

[0140] Results for vancomycin and compound 13 are presented in Table 5.

[0141] What is more, pharmacokinetic studies show that compound 13exhibits an unexpectedly greater bioavailability, faster clearance rateand/or more favorable tissue distribution than the bioavailability,clearance rate and/or tissue distribution observed for compound 2, whichbears a chlorobiphenyl substituent on the amine nitrogen of vancosamine.These results indicate an improved likelihood that compound 13 and theother compounds listed in Table 2 might succeed in the clinic.

[0142] 5.9. Additional Examples of Compounds of the Invention

[0143] As a further illustration of the types of compounds contemplatedby the present invention, a Chart (Table 6) is provided listing over onehundred compounds.

[0144] The following definitions are set forth for clarification of theinvention. DMF N,N-dimethylformamide THY tetrahydrofuran TFAtrifluoroacetic acid EtOAc ethyl acetate MeOH methanol MeCN acetonitrileTf trifluoroacetyl group DMSO dimethyl sulfoxide DIEAdiisopropylethylamine All in structural formulas refers to allyl groupHOBt 1-hydroxybenzotriazole CBz benzyloxycarbonyloxy Su succinimidylgroup Alloc allyloxycarbony

[0145] TABLE 1 Compounds 1-12 Ret. Time Entry K Ar1 Z Ar2 NR₂R₃ (M +H)²⁺ 1

—NH₂ 1.31 min. (835) 2 —CH₂—

bond

—NH₂ 1.21 min. (824) 3 —CH₂—

bond

1.21 min. (853) 4 —CH₂—

bond

1.22 min. (860) 5 —CH₂—

bond

1.21 min. (860) 6 —CH₂—

bond

1.22 min. (873) 7 —CH₂—

bond

1.21 min. (860) 8 —CH₂—

bond

1.16 min. (888) 9 —CH₂—

bond

1.22 min. 10 —CH₂—

bond

1.24 min. (901) 11 —CH₂—

bond

1.20 (882) 12 —CH₂—

bond

1.17 min. (898)

[0146] TABLE 2 Compounds 13-24 Ret. Time Entry K Ar1 Z Ar2 NR₂R₃ (M +H)²⁺ 13 —CH₂—

—OCH₂—

—NH₂— 1.39 min. (857) 14 —CH₂—

—OCH₂—

1.38 min. (902) 15 —CH₂—

—OCH₂—

1.39 min. (886) 16 —CH₂—

—OCH₂—

1.40 min. (892) 17 —CH₂—

—OCH₂—

1.40 min. (892) 18 —CH₂—

—OCH₂—

1.41 min. (905) 19 —CH₂—

—OCH₂—

1.40 min. (892) 20 —CH₂—

—OCH₂—

1.34 min. (921) 21 —CH₂—

—OCH₂—

1.42 min. (933) 22 —CH₂—

—OCH₂—

1.43 min. (933) 23 —CH₂—

—OCH₂—

1.39 (914) 24 —CH₂—

—OCH₂—

1.35 min. (931)

[0147] TABLE 3 Bacterial Strains for Assays Phenotype^(b) Strain Van^(c)Gent Amp 1pm Source Enterococci E. faecium RLA1 S S R R Dr. B. Murray,Houston, TX E. faecium CL 4931 (VanA) R R R R NY Hospital, NYC E.faecium CL 5053 (VanA) R R R R Bellevue Hospital, NYC E. faecium CL 5242(VanA) R R R R Dr. Sahm, Wash. Univ. School of Med E. faecalis MB2864 SS S S Merck Clinical Culture Collection E. faecalis CL 4877 (VanB) R R SS/I Univ. of Maryland Hospital, Baltimore, MD E. faecalis CL 5244 (VanB)R S S S Merck Clinical Culture Collection E. gallinarum CL 4886 (VanC) IR S S Dr. Shlaes, Cleveland VA Hospital Staphylococci MSSA MB2985^(a) SS S S Mouse pathogen (Smith strain) MRSA CL 3033 S R R VA Hospital, EastOrange, NJ MRSA COL S S R R Dr. A. Tomasz, Rockefeller Univ., NYC MRSAMH 76 VISA/MRSA CL 5705 S R R R Mu 3; Dr. K. Hiramatsu, Juntendo Univ.,Japan VISA/MRSA CL 5706 I R R R Mu 50; Dr. K. Hiramatsu, Juntendo Univ.,Japan MRCNS (S. epi.) CL 3069 S R Univ. of Texas MRCNS (S. hom.) CL 227S R Temple Univ. Hosp., Philadelphia, PA MRCNS (S. haem.) CL 171 S RTemple Univ. Hosp., Philadelphia, PA MRCNS (S. haem.) CL 202 S R TempleUniv. Hosp., Philadelphia, PA MRCNS (S. hom.) CL 546 S R Wilmington Med.Center, Delaware Gram-negative strains E. coli (envA*) ASP #49 R Tet^(R)envA* MB2884 (M. Salvatore/N. Lee) E. coli (envA*) ASP #50 R Tet^(R)envA* MB2884 (M. Salvatore/N. Lee)

[0148] Antibiotic Susceptible Intermediate Resistant Vancomycin ≦4 8-16≧32 (all but Enterobacteriaceae) Gentamicin (enterococci) ≦500 — >500Gentamicin ≦4 8 ≧16 (all but enterococci) Ampicillin (enterococci) ≦8 —≧16 Ampicillin (staphylococci) ≦0.25 — ≧0.5 Ampicillin ≦8 16 ≧32(Enterobacteriaceae) Imipenem ≦4 8 ≧16 (all but enterococci)

[0149] TABLE 4 Summary of MICs of Compound 13 MIC (μg/ml) 13 13 13Strain Vancomycin ^(b) #1 #2 #3 E. faecium RLA1 2 <0.03 0.008 0.016 CL4931 (VanA) 2048 2 0.5 1 CL 5053 (VanA) 2048 1 1 2 CL 5242 (VanA) 1280.06 0.25 0.5 E. faecalis MB2864 2 ≦0.03 0.12 0.25 CL 4877 (VanB) 20480.25 2 2 CL 5244 (VanB) 32 0.12 0.25 0.25 E. gallinarum CL 4886 16 10.25 1 MSSA ^(a) MB2985 1 ≦0.03 0.008 0.016 MB2985 + HAS 1 ≦0.03 0.0080.008 (N-fold MIC (1)  (1)   (0.5) inc. + HSA) MRSA CL 3033 0.5-1   0.250.12 0.12 COL 1 0.25 0.12 0.25 MH 76 1 0.25 0.25 0.25 VISA/MRSA CL 5705 2-4 0.5 0.12 0.25 CL 5706  4-8 0.5 0.12 0.5 MRCNS CL 3069 (S. epi.) 20.06 0.03 0.06 CL 227 (S. hom.) 1 0.06 0.016 0.016 CL 171 (S. haem.) 2≦0.03 0.03 0.06 CL 202 (S. haem.) 2 0.12 0.06 0.06 CL 546 (S. hom.) 1≦0.03 0.016 0.016 E. coli ASP #49 (envA⁻) 32 16 16 8 ASP #50 (envA⁺)256 >64 64 64

[0150] TABLE 5 Results of In Vivo Studies Compound VAN 13 % Plasma Bound55 nt Test Organism S. aureus S. aureus MB# 2985 2985 MIC (μg/ml) 0.50.125 # of Doses 1 (0 hr) 1 (0 hr) # of LD₅₀'s 69 69 ED₀ (s.c., mg/kg)≦0.195 0.195 ED₅₀ (s.c., mg/kg) 1.167 0.390 ED₁₀₀ (s.c., mg/kg) 3.1250.780 ED₅₀/MIC 2.33 3.12 95% C.L. 0.67-2.03 Nd

[0151] Table 6 Chart of Additional Compounds 1-132 Example K Ar₁ Z Ar₂ R1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

Examples 133-170

[0152] Using the preparatory procedures set forth above, the followingsubstituted compounds 133-171 of this invention are prepared and tested.In these compounds, K—Ar₁-Z-Ar₂ is (3,4-dichlorobenzyloxy)benzyl, andthe polar group R is as described in the following Table 7 of compoundsof the invention. The results of in vitro testing of vancomycin andteicoplanin against strains of various bacteria are also set forth.TABLE 7 Compound CL4931 CL5053 CL5242 CL4877 Mean R vanco 2048 2048 5122048 1664.0 telco 256 >1024 256 0.5 170.8 133 2 2 0.5 0.03 1.14-aminophenylmethylene 134 2 4 1 0.25 1.8 phenylmethylene 135 4 4 1 0.062.3 4-aminophenylethylene 136 4 4 1 0.12 2.3 4-fluorophenylmethylene 1374 4 1 0.12 2.3 3-chlorophenylmethylene 138 8 4 1 0.5 3.44-methoxyphenylmethylene 139 8 4 2 0.25 3.6 2-aminophenylmethylene 140 48 2 0.5 3.6 2-piperidylmethylene 141 4 8 2 1 3.8 4-methylphenylmethylene142 4 8 2 2 4.0 2-tetrahydrofuranylmethylene 143 8 4 2 2 4.0phenylethylene 144 4 8 2 2 4.0 cyclopentyl 145 8 8 1 0.5 4.42-furanomethylene 146 8 8 1 0.5 4.4 hydroxyethylene 147 4 8 2 4 4.5methyl 148 8 8 1 1 4.5 n-propyl 149 8 8 2 0.25 4.64-chlorophenylmethylene 150 8 8 2 4 5.5 allyl 151 8 16 2 0.5 6.6phenylmethylenecarbonyl 152 16 8 2 1 6.8 naphthyl 153 8 16 4 0.12 7.02-chlorophenylmethylene 154 16 16 4 0.5 9.1 2-hydroxynaphthyl 155 16 164 1 9.3 4-piperidylmethylene 156 16 16 2 4 9.52-tetrahydropyranomethylene 157 16 16 4 4 10.0 cyanoethylene 158 16 16 44 10.0 3,4-dichlorophenylmethylene 159 16 16 4 4 10.0 isobutylene 160 1616 4 16 13.0 3-(N-pyrrolidinylpropylene 161 16 16 4 16 13.0aminopropylene 162 16 16 4 16 13.0 2-(2-hydroxy)-tetrahydrofuranylmethylene 163 16 32 4 2 13.5 pyrrolidinyl 164 16 16 816 14.0 3-thiophenesulfone 165 16 16 8 16 14.0 cyclopropanyl 166 8 16 232 14.5 3-dimethylaminopyrrolidinyl 167 8 16 4 32 15.0 piperazinyl 16832 16 8 1 18.3 piperidinyl 169 32 32 8 1 18.3 morpholinyl 170 16 32 8 3222.0 4-dimethylaminopiperidinyl

Examples 171-189

[0153] Using the preparatory procedures set forth above, the followingsubstituted compounds 171-189 of this invention were prepared and testedas described. In these compounds, the polar group R is amino, andK—Ar₂-Z-Ar₂ is as shown in the following Table 8 of compounds of theinvention. The results of in vitro testing of vancomycin and teicoplaninagainst strains of various bacteria are also set forth. TABLE 8K—Ar₂-Z-Ar₂ CL4931 CL5053 CL5242 CL4877 Mean 1714-(4-chlorobenzyloxybenzyl) 4 8 1 16 7.25 1724-(3-chlorobenzyloxy)benzyl 16 16 2 >16 12.5 1734-(2,4-dichlorobenzyloxy)benzyl 8 8 1 2 4.75 1744-(2,5-dichlorobenzyloxy)benzyl 16 16 8 16 14 1754-(3,5-dichlorobenzyloxy)benzyl 4 4 2 2 3 1764-(2,6-dichlorobenzyloxy)benzyl 16 16 4 >16 13 1774-(4-methoxycarbonylbenzyloxy)benzyl >16 >16 4 >16 13 1784-(4-nitrobenzyloxy)benzyl 32 >32 8 >32 27 1794-(4-trifluoromethylbenzyloxy)benzyl 8 8 1 4 3.25 1804-(2-trifluoromethylbenzyloxy)benzyl 16 16 2 16 12.5 1814-(2-chloro-4-fluoro-benzyloxy)benzy 16 32 4 32 21 1824-(2-chloro-benzyloxy)benxyl >16 >16 4 >16 13 1832-chloro-4-(3,4-dichlorobenzyloxy) 8 4 2 2 4 benzyl 1843-methoxy-4-(-3,4-dichlorobenzyloxy) 4 4 2 8 4.5 benzyl 1852-methoxy-4(3,4-dichlorobenzyloxy) 8 16 4 4 8 benzyl 1864-(3,4-dichlorophenoxy)benzyl 8 8 2 8 6.5 1874-(4-chlorophenoxycarbonyl)benzyl 16 16 4 32 17 1884-(3,4-dichlorophenoxycarbonyl)benzyl 8 16 4 16 11 1894-(3,4-dichlorophenyl)phenoxy 32 >32 32 32 32 carbonylmethyl

Examples 190-198

[0154] Using the preparatory procedures set forth above, the followingsubstituted compounds 190-198 of the invention are prepared and testedas described. In these compounds, K-Ar₂-Z-Ar₂ is4(para-chlorophenyl)benzyl, and the polar groups R are as shown in thefollowing Table 9 of compounds of the invention. The results of in vitrotesting of vancomycin and teicoplanin against strains of variousbacteria are also set forth. TABLE 9 compound CL4931 CL5053 CL5242CL4877 Mean K—Ar₂-Z-Ar₂ vanco 2048 2048 512 2048 1664.0 teico 256 >1024256 0.5 128.1 190 8 8 2 4 5.5 phenylmethylene 191 16 16 4 16 13.02-pyridylethylene 192 16 16 4 16 13.0 2-tetrahydrofuranylmethylene 19316 16 4 16 13.0 3-dimethylaminoazolinyl 194 8 16 2 16 22.9 n-propyl 19532 32 8 32 26.0 N-pyrrolyl 196 32 32 16 32 26.0 morpholinyl 197 16 32 832 25.0 piperazinyl 198 32 32 16 32 28.0 piperidinyl

Examples 199-215

[0155] Using the preparatory procedures set forth above, the followingsubstituted compounds 199-215 are prepared and tested as described. Inthese compounds R¹ is 4-(3,4-dichlorophenyl)benzyl, and the polar groupR is as shown in the following Table 10. The results of in vitro testingof vancomycin and teicoplanin against strains of various bacteria arealso set forth. TABLE 10 compound CL4931 CL5053 CL5242 CL4877 Mean Rvanco 2048 2048 512 2048 1536.0 teico 256 >1024 256 16 256.0 199 4 4 0.52 2.6 2-hydroxyethylene 200 4 4 1 2 2.8 4-fluorophenylmethylene 201 4 41 4 3.3 2-tetrahydrofuranmethylene 202 4 8 1 2 3.83-fluorocyclopentylene 203 8 8 1 2 4.8 phenylmethylene 204 8 8 1 2 4.82-furanolmethylene 205 8 8 2 2 5.0 cyclopropylene 206 8 8 1 4 5.3 methyl207 8 8 2 4 5.5 ethyl 208 8 4 2 8 5.5 (2-thiophene)methylene 209 8 8 2 45.5 2-chlorophenylmethylene 210 16 8 2 4 7.5 4-aminophenylmethylene 21116 8 4 4 8.0 3-chlorophenylmethylene 212 16 8 4 4 8.02-aminophenylmethylene 213 16 16 4 8 11.0 2-pyridylmethylene 214 16 16 48 11.0 4-pyridylmethylene 215 32 32 4 32 25.0 piperazino

[0156] The invention has been described herein with reference to certainpreferred embodiments. However, as obvious variations thereon willbecome apparent to those skilled in the art, the invention is not to beconsidered as limited thereto.

What is claimed is:
 1. A vancomycin analog whose glucose C-6 position ismodified to bear a polar substituent other than a naturally occurringhydroxyl group and whose vancosamine is substituted at the aminenitrogen with a lipid-like substituent having at least a first arylmoiety and second aryl moiety joined together by a first flexible linkermoiety that it is not a single bond, directly joining the first arylmoiety and the second aryl moiety or a pharmaceutically acceptable saltthereof.
 2. The analog of claim 1 in which a second flexible linkermoiety, the same as or different from the first, joins the aminenitrogen of the vancosamine and the first aryl moiety of the lipid-likesubstituent.
 3. The analog of claim 1 in which the lipid-likesubstituent falls within the scope of the formula K—Ar₁-Z-Ar₂, in whichAr₁ and Ar₂ represent a first aryl moiety and a second aryl moiety,respectively, and K and Z represent a second flexible linker moiety anda first flexible linker moiety, respectively, provided that Z is not asingle bond joining Ar₁ and Ar₂.
 4. The analog of claim 1 in which thelipid-like substituent comprises a benzyloxybenzyl group.
 5. The analogof claim 4 in which said benzyloxybenzyl group is further substituted byone or more halide groups.
 6. The analog of claim 1 in which the polarsubstituent is a free amine.
 7. The analog of claim 1 in which the polarsubstituent is a substituted amine that provides for a primary orsecondary amine at a distal position.
 8. The analog of claim 1 in whichthe polar substituent is charged at or about physiological pH.
 9. Theanalog of claim 1 having the Formula I, below:

in which the group K—Ar₁-Z-Ar₂ is as described above, provided that Z isnot a single bond directly joining Ar₁ and Ar₂.
 10. The analog of claim9 in which the group K is a CH₂.
 11. The analog of claim 10 in which thegroup Z is an OCH₂.
 12. The analog of claim 11 in which Ar₁ isphenylene.
 13. The analog of claim 12 in which Ar₂ is dichlorophenyl.14. The analog of claim 13, which is:


15. The analog of claim 1, which is:Glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,N-(3-Pyridyl)methyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,N-Glycyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,N-L-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,orN-D-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,or pharmaceutically acceptable salts thereof.
 16. The analog of claim 1,which is:N-L-Prolyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,N-8-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,N-L-Lysyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,N-L-(3-thiazolyl)alanyl-glucos-6-amino-N-4(3,4-dichlorobenzyloxy)benzyl-vancosaminovancomycin,N-L-(2-thienyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,N-L-Asparagyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,or N-D-(3-pyridyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin or pharmaceutically acceptablesalts thereof.
 17. An analog of claim 3 wherein K and Z are selectedfrom the group consisting of carbonyl, sulfonyl, (C₁₋₆)alkylene,(C₁₋₆)alkyleneoxy, oxy(C₁₋₆)alkylene, (C₁₋₆)alkyleneamino,amino(C₁₋₆)alkylene, (C₁₋₃)alkyleneoxy-(C₁₋₃)alkylene,(C₁₋₆)alkylenethio, thio(C₁₋₄)alkylene, (C₁₋₆)alkylenecarbonyl,aminocarbonyl or carbonylamino, (C₁₋₆)alkyleneaminocarbonyl,aminocarbonyl(C₁₋₆)alkylene, oxy, oxycarbonyl or carbonyloxy,(C₁₋₆)alkyleneoxycarbonyl, oxycarbonyl(C₁₋₆)alkylene, aminosulfonyl, orsulfonylamino.
 18. An analog of claim 3 wherein Ar₁ and Ar₂ may be thesame or different are selected from the group consisting of aromatic orheterocyclic groups, each optionally monosubstituted, disubstituted, ortrisubstituted with R₁; wherein R₁ can be halo; R₂; CN; NO₂; CF₃;OCH_(x)F_((3-x)(x=0-3)); NHSO₂R₂; OR₂, SR₂; N(R₂)₂; N⁺(R₂)₃; C(O)N(R₂)₂;SO₂N(R₂)₂; heterocyclic; CO₂R₂; C(O)R₂; OC(O)R₂; NR₂C(O)R₂; or NHC(O)R₂;and wherein R₂ independently (where more than one R₂ is present)represents H, aryl, straight or branched (C₁₋₆)alkyl, arylalkyl,heterocyclic, heterocyclic(C₁-C₆)alkyl, aroyl, alkanoyl, alkanoyloxy,alkanoylamido, alkylsulfonyl, arylsulfonyl; and when two R₂ groups arepresent, they may optionally be linked by one or more covalent bonds toform one or more rings, which may be aromatic, aliphatic, orheterocyclic.
 19. An analog according to claim 1, wherein the C₆ polarsubstituent is a group R which has the formula:

in which the groups R₃ and R₄ may independently be present or absentand, if present, may be the same or different and selected from thegroup consisting of H, alkyl, aryl, heterocyclic, aralkyl,heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, heterocycliccarbonyl,aminocarbonyl, substituted aminocarbonyl, substituted oxycarbonyl,alkylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, aminosulfonyl,substituted aminosulfonyl, amidino, or substituted amidino, said alkyl,aryl, heterocyclic, arylalkyl, heterocyclicalkyl, alkylcarbonyl,arylcarbonyl, or heterocycliccarbonyl being optionally substituted with1-3 groups of R₁; and wherein R₃ and R₄ may be linked to one another orto one or both of the others by one or more covalent bonds to form oneor more aryl or heterocyclic rings of 3-20 members, optionally comprisedof C, N, O, or S.
 20. An analog of claim 3 wherein K and Z ofK—Ar₁-Z-Ar₂ are selected from the group consisting of carbonyl,sulfonyl, (C₁₋₆)alkylene, (C₁₋₆)alkyleneoxy, oxy(C₁₋₆)alkylene,(C₁₋₆)alkyleneamino, amino(C₁₋₆)alkylene,(C₁₋₃)alkyleneoxy-(C₁₋₃)alkylene, (C₁₋₆)alkylenethio,thio(C₁₋₆)alkylene, (C₁₋₆)alkylenecarbonyl, aminocarbonyl orcarbonylamino, (C₁₋₆)alkyleneaminocarbonyl, aminocarbonyl(C₁₋₆)alkylene,oxy, oxycarbonyl or carbonyloxy, (C₁₋₆)alkyleneoxycarbonyl,oxycarbonyl(C₁₋₆)alkylene, aminosulfonyl, or sulfonylamino.
 21. Ananalog of claim 20 wherein Ar₁ and Ar₂ of K—Ar₁-Z-Ar₂ may be the same ordifferent are selected from the group consisting of aromatic orheterocyclic groups, each optionally monosubstituted, disubstituted, ortrisubstituted with R₁; wherein R₁ can be halo; R₂; CN; NO₂; CF₃;OCH_(x)F_((3-x)(x=0-3)); NHSO₂R₂; OR₂, SR₂; N(R₂)₂; N⁺(R₂)₃; C(O)N(R₂)₂;SO₂N(R₂)₂; heterocyclic; CO₂R₂; C(O)R₂; OC(O)R₂; NR₂C(O)R₂; or NHC(O)R₂;and wherein R₂ independently (where more than one R₂ is present)represents H, aryl, straight or branched (C₁₋₆)alkyl, arylalkyl,heterocyclic, heterocyclic(C₁-C₆)alkyl, aroyl, alkanoyl, alkanoyloxy,alkanoylamido, alkylsulfonyl, arylsulfonyl; and when two R₂ groups arepresent, they may optionally be linked by one or more covalent bonds toform one or more rings, which may be aromatic, aliphatic, orheterocyclic.
 22. An analog according to claim 21, wherein the C₆ polarsubstituent is a group R which has the formula:

in which the groups R₃ and R₄ may independently be present or absentand, if present, may be the same or different and selected from thegroup consisting of H, alkyl, aryl, heterocyclic, aralkyl,heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, heterocycliccarbonyl,aminocarbonyl, substituted aminocarbonyl, substituted oxycarbonyl,alkylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, aminosulfonyl,substituted aminosulfonyl, amidino, or substituted amidino, said alkyl,aryl, heterocyclic, arylalkyl, heterocyclicalkyl, alkylcarbonyl,arylcarbonyl, or heterocycliccarbonyl being optionally substituted with1-3 groups of R₁; and wherein R₃ and R₄ may be linked to one another orto one or both of the others by one or more covalent bonds to form oneor more aryl or heterocyclic rings of 3-20 members, optionally comprisedof C, N, O, or S.
 23. An analog according to claim 9, wherein the groupK is (C₁-C₆) alkylene oxy and the polar group R is amino.
 24. An analogof claim 15, which isGlucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycinor pharmaceutically acceptable salts thereof.
 25. An analog of claim 15which isN-(3-Pyridyl)methyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,or pharmaceutically accepable salts thereof.
 26. An analog of claim 15which isN-Glycyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycinor pharmaceutically acceptable salts thereof.
 27. An analog of claim 15which isN-L-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycinor pharmaceutically acceptable salts thereof.
 28. An analog of claim 15which isN-D-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycinor pharmaceutically acceptable salts thereof.
 29. An analog of claim 16which isN-L-Prolyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,or pharmaceutically acceptable salts thereof.
 30. An analog of claim 16which isN-B-Alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,or pharmaceutically acceptable salts thereof.
 31. An analog of claim 16which isN-L-Lysyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycinor pharmaceutically acceptable salts thereof.
 32. An analog of claim 16which isN-L-(3-thiazolyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,or pharmaceutically acceptable salts thereof.
 33. An analog of claim 16which isN-L-Asparagyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,or a pharmaceutically acceptable salt thereof.
 34. An analog of claim 16which isN-L-(2-thienyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,or a pharmaceutically acceptable salt thereof.
 35. An analog of claim 16which isN-D-(3-pyridyl)alanyl-glucos-6-amino-N-4-(3,4-dichlorobenzyloxy)benzyl-vancosamino-vancomycin,or a pharmaceutically acceptable salt thereof.
 36. An analog accordingto claim 3, wherein K—Ar₁-Z-Ar₂ is 4-(3,4-dichlorobenzyloxy)benzyl, andR is selected from the group consisting of aminophenylmethylene,phenylmethylene, aminophenylethylene, fluorophenylmethylene,chlorophenylmethylene, methoxyphenylmethylene, 2-piperidylmethylene,methylphenylemethylene, 2-tetrahydrofuranylmethylene, phenylethylene,cyclopentyl, 2-furanomethylene, hydroxyethylene, methyl, n-propyl,allylyl, phenylmethylcarbonyl, and naphthyl.
 37. An analog according toclaim 3, wherein K—Ar₁-Z-Ar₂ is 4-(3,4-dichlorobenzyloxy)benzyl, and Ris selected from the group consisting of chlorobenzyl, 2-hydroxyindanyl,4-pyridiylmethylene, 2-morpholinomethylene, cyanoethyl,3,4-dichlorobenzyl, 2-methylpropyl, N-(2-oxazolyl)-n-propyl,2-(2-hydroxyltetrahydrofuranyl) methyl, azolinyl,3-thiazofuranyldioxide, cyclopropanyl, 3-amino-N-azolyl, N-piperazinyl,N-piperidinyl, N-morpholino, and N-(4-diaminopiperazinyl).
 38. An analogaccording to claim 3, wherein R is NH₂, K is —CH₂—, Ar₁ is phenylene, Zis —O—CH₂—, and Ar₂ is selected from the group consisting of(p-carbonyloxymethylester), phenyl, p-nitrophenyl,p-trifluoromethylphenyl, o-trifluoromethylphenyl,1-chloro-3-fluorophenyl, and 2-chlorophenyl.
 39. An analog according toclaim 3, wherein R is NH₂, K is CH₂, Z is —O—CH₂—, Ar₂ is3,4-dichlorophenyl, and Ar₁ is selected from the group consisting of2-chlorophenylene, 2-methoxyphenylene and 3-methoxyphenylene.
 40. Ananalog according to claim 3, wherein R is NH₂, K is CH₂, Ar₁ is phenyl,Z is —C(O)—O—, and Ar₂ is p-chlorophenyl or 3,4-dichlorophenyl.
 41. Ananalog of claim 9, wherein Ar₂ is 3,4-dichlorophenyl, Z is —OCH₂—, Ar₁is phenylene, R is NH₂ and K is selected from the group consisting of—CH₂—, —C(O)—, —SO₂—, —CH₂CH₂—, —C(O)CH₂—, —CH₂C(O)—, —CH₂CH₂CH₂—,—CH₂CH₂O—, —CH₂CH₂S—, —C(O)O—, —C(O)NH—, and —C(O)N(CH₃)—.
 42. An analogof claim 9, wherein R is NH₂, K is —CH₂—, Z is —OCH₁₂—, Ar₂ is3,4-dichlorophenyl and Ar₁ is selected from the group consisting of:


43. An analog according to claim 9, wherein R is NH₂, K is —CH₂—, Ar₁ isphenylene, Ar₂ is 3,4-dichlorophenylene and Z is selected from the groupconsisting of —CH₂—, —C(O)—, —SO₂—, —S(O)— —S—, —O—, —C₁H₂O—, —C═C—,—C═C—, —CH₂CH₂CH₂—, —C(O)CH₂CH₂—, —CH₂CH₂C(O)—, —OCH₂CH₂—, —CH₂CH₂O—,—CH₂OCH₂—, —C(O)NH—, —C(O)N(CH₃)—, —SO₂N(CH₃)—, —SO₂NH—, —NHSO₂—,—N(CH₃)SO₂—, —NHC(O)—, —N(CH₃)C(O)—, —C(O)OCH₂—, —CH₂OC(O)—,—CH₂NHC(O)—, —CH₂N(CH₃)CO—, —C(O)N(CH₃)CH₂—, —C(O)NHCH₂—, —SO₂NHCH₂—,—SO₂N(CH₃)CH₂—, —CH₂N(CH₃)SO₂—, and —CH₂NHSO₂—.
 44. An analog accordingto claim 9, wherein R is NH₂, K is —CH₂—, Ar₁ is phenylene, Z is —OCH₂—and Ar₂ is selected from the group consisting of:


45. An analog according to claim 9, wherein K—Ar₁-Z-Ar₂ is4-(3,4-dichlorobenzyloxybenzyl) and R is selected from the groupconsisting of:


46. A pharmaceutical composition comprising the analog of claim 1 or itspharmaceutically acceptable salt in combination with a pharmaceuticallyacceptable carrier.
 47. A method of treating or preventing a bacterialinfection in a mammalian patient in need thereof, comprisingadministering to said patient an effective amount of the analog of claim1.